In this chapter we shall address many of the practices and procedural issues that affect and control the production, supply and clinical use of biomaterials and products that are based on these materials. These are not trivial matters. They should be considered as essentials, rather than as afterthoughts or “nice-to-haves.” The reason why these issues are addressed towards the end of this book and not at the beginning is a reflection of the need for the reader to first understand the essential scientific, clinical and technological basis before coming to grips with the infrastructure issues, rather than any suggestion of lesser importance. This chapter covers the regulation of biomaterials-based health care products, the pre-clinical testing and clinical evaluation of materials and products, and the ethical, legal and economic matters that have a major influence over this industry.

Introduction

Although it could be argued that, globally, the biomaterials and medical technology industries are quite heterogeneous and fragmented, there are several facets of the industry that are highly structured. These deserve discussion in a textbook on the essentials of biomaterials science. The fundamental reason for this is that biomaterials can do harm as well as good and it is essential that they are used as safely and effectively as possible. This will not happen if each application of a medical device that incorporates biomaterials is developed in isolation, in ignorance of the relevant history of that type of device and without regard to the broader issues of patient (and doctor) safety and the ethical and legal aspects of clinical applications. That there are standards and codes of practice in industrial sectors where safety is a primary concern, such as in aerospace and nuclear industries, is no surprise. The sheer volume of medical devices used on a global scale, and the potential number of individuals that they can affect, for good or bad, suggests that there should be extensive control over these products as well.

After studying this chapter you will be able to identify all of the significant applications of biomaterials in those devices that replace the structure and/or function of tissues and organs by the use of medical devices. These may be implanted within the patients, usually for the remainder of their lives, or connected to the patient for some short-term assistance; these applications were summarized at the end of Chapter 1. This discussion covers all of the clinical disciplines. It includes implantable devices that have been in use for decades, and you will be able to understand the reasons for their success, and the reasons for failures where they have occasionally occurred. It also covers the implantable and support systems that have recently been developed and introduced into clinical practice so that you can appreciate where the technology of the twenty-first century is leading us in health care products.

As noted earlier, implantable medical devices were, for many years, the main focus of attention within biomaterials science. The rationale and performance of such devices are discussed in this chapter. Each application and each situation is different and it is not possible to deal with this in an entirely satisfactory systematic manner, but the major headings given in Chapter 1 are covered and dealt with in relation to the clinical discipline that is involved. This includes permanent (or long-term) devices, short-term devices, invasive but removable devices and artificial organs or assist devices that are attached to the body. We will conclude the chapter with an assessment of the overall performance of implantable devices and the lessons learned.

Biocompatibility is the most critical factor that controls the success of biomaterials and those health care products that incorporate biomaterials. It is concerned with the mechanisms of interaction between biomaterials and the human body, and the consequences of these interactions. This chapter first introduces the concept of biocompatibility and then provides you with a series of scenarios that cover the whole range of situations in which biomaterials come into contact with tissues. In each case, critical mechanisms are explained and discussed, leading to the presentation of a unified framework of the sequence of events that constitute biocompatibility. This is based on the simple concept that in biocompatibility there are causative events within the biomaterial–host interactions that lead, through a variety of different but interconnected pathways, to physiological or pathological effects and then to their clinical consequences. This framework is then used to explain a variety of situations in which biocompatibility has proved to be so important.

Introduction

We discuss here a wide variety of situations in which interactions take place between biomaterials and the patients in which they are placed, and where the nature of that interaction determines both the level of satisfaction and risk that the patient receives or perceives.

In this opening chapter you will be introduced to the extent to which health care products contribute to the delivery of therapeutic and diagnostic procedures across a massive array of clinical problems and solutions. Included here are examples of long-term implantable devices, procedures of regenerative medicine, the diagnosis of disease and injury, and the specialized delivery of drugs and genes. You will then see how biomaterials science has evolved in order to optimize the performance of these products. The concepts of biomaterials science are introduced, along with a general discussion of the requirements of biomaterials and their essential characteristics.

Health care products in medical practice

You are an observer in a busy doctor’s clinic on a Monday morning during a cold wet month of the winter. This is a large polyclinic, which includes not only primary care physicians but a plethora of specialists, who deal with the diagnosis and uncomplicated treatments for a variety of conditions, ranging from dental and ophthalmological conditions, to neonatal care, trauma, geriatric complaints and common infectious diseases. A few hundred meters away is a major teaching hospital, able to deal with virtually every acute and chronic condition that is likely to be seen in this mid-size industrial city, which encompasses people of all ages and genetic background.

Vascular endothelial cells are cultured on the inside of a 10-cm long hollow tube that has aninternal diameter of 3 mm. Culture medium flows through the tube at Q= 1 ml/s. The cells produce a cytokine, EDGF, at a rate nEDGF (production rate per cell area) that depends on the local wall shear stressaccording to nEDGF = kτwall, wherek is an unknown constant with units of ng/dyne per s. The flow in the tubeis not fully developed, such that the shear stress is known to vary with axial position according toτwall = τ0(1 –βx), where β= 0.02 cm−1, τ0= 19 dyne/cm2, and x is the distance from the tubeentrance. Under steady conditions a sample of medium is taken from the outlet of the tube, and theconcentration of EDGF is measured to be 35 ng/ml in this sample. What isk?

Flow occurs through a layer of epithelial cells that line the airways of the lung due to avariety of factors, including a pressure difference across the epithelial layer(ΔP = P0) and, in the case of transientcompression, to a change in the separation between the two cell membranes, w2, as a function of time. We consider these cases sequentially below. Note that the depthof the intercellular space into the paper is L, and the transition in cellseparation from w1 to w2 occurs over alength δ much smaller than H1 andH2. (See the figure overleaf.)

Consider a membrane of thickness 10 μm that has a number of tiny cylindrical pores (of radius 10 nm) passing through it. The density of pores in the membrane is such that the porosity (fractions of water-filled space) of the membrane is 0.1%.

1. (a) Find the hydraulic conductivity (Lp, flow rate per unit area per unit pressure drop) of this membrane.

2. (b) Consider a 4 mM solution of a large protein on one side of this membrane and physiologic saline on the other, with the same pressure on both sides of the membrane. Assume that the protein is sufficiently large that it cannot pass through the membrane and that van ’t Hoff’s law holds for this solute. Calculate the initial flow rate of saline through a membrane of area 5 cm2 at a temperature of 300 K.

The graph shown in the figure overleaf is adapted from a 1927 paper [16] in which Landis proved the existence of Starling’s phenomenon by occluding capillaries. The ordinate is the volume of fluid leaking out of (or re-entering) the capillary per unit capillary wall area, j. Although it is not precisely true, for the purposes of this question you may assume that the reflection coefficient of this capillary wall to plasma proteins is unity.

1. (a) Assuming that p – Π for the interstitium is –5 cm H2O, estimate the plasma osmotic pressure (Π) from the figure. Note that the plasma proteins are the main species influencing the osmotic pressure difference across the capillary wall.

2. (b) Estimate the filtration coefficient Lp for this capillary.

3. (c) Consider a capillary 0.05 cm long of diameter 8 µm, for which the arteriolar and venular luminal pressures are 25 and 5 cm H2O, respectively. Assume that Lp and Π are constant and that the pressure drop varies linearly along the capillary. What is the net rate of fluid loss (gain) from the capillary?